Genetic disorders are triggered by changes occurring in your DNA. These changes – commonly referred as gene mutations – can make your DNA to assume a sequence that is quite different from its usual code. With the development of modern clinical sciences, the role of genes in almost all ailments is currently studied with greater focus. Pfeiffer syndrome is very a rarely observed genetic disorder. What causes Pfeiffer syndrome? Can Pfeiffer syndrome be corrected? If it can be corrected, what are the ways in which it can be treated? Answers to all these questions can help build needful understanding about this medical condition and the approaches available to treat it.

Genetic disorders are triggered by changes or mutations of genes; they can be caused due to mutations of multiple genes or a single gene. Changes in multiple genes are called polygenic and those occurring in a single gene are termed monogenic mutations. Mutation of genes may be from one of the parents who has a disorder or from both parents who happen to be carriers of the mutated gene(s). Apart from these, genetic disorders may also be triggered by abnormal chromosomes. Most of the genetic medical conditions are uncommon in occurrence. In all, there are more than 5,500 disorders identified due to genetic mutations or abnormal chromosomes.

Pfeiffer syndrome is a very uncommon type of disorder. Its incidence is observed in 1 among 100,000 children. It is known to be caused due to mutations of a gene. The most common factor is attributed to mutations of a gene called FGFR2; though mutations in a gene labelled as FGFR1 may also be reason for type 1 form of this disorder.

What causes Pfeiffer syndrome?

Medical conditions caused by genetic mutations need one copy of a changed or mutated gene to trigger a genetic condition. The child may be the first in a family to experience this mutated gene or it may have been passed on from the child’s parent(s). So, what exactly causes a condition like Pfeiffer syndrome? This condition is mostly triggered by a new change or mutation in the baby’s genes. It is because most of the affected babies’ parents are known to be carriers of a mutated gene. However, a small minority of cases are due to either one of the parents acting as a carrier. As per prominent craniofacial forums and associations, the odds of a parent living with Pfeiffer syndrome to pass the gene to her / his child are 50%.

Pfeiffer syndrome is a condition that interferes in the proper development of your skull. Its normal growth stands interrupted by this syndrome. Owing to this, face and head of babies with this syndrome do not take a normal shape. Not stopping with bones of the skull, Pfeiffer syndrome can also affect bones in the feet and hands. It commonly shows up as an early or untimely fusion of the bones of the skull. As a result, you may have a raised forehead and wide-set, bulged eyes. Nose often takes a beaked form with the upper part of the jaw not fully developed. As a side effect, dental health issues are common among children with Pfeiffer syndrome. A significant percentage (> 52%) may also have hearing impairment. You may also notice the big toe (i.e., first toe) and thumb are spaced away from your other toes and fingers. Your digits (i.e., both toes and fingers) may be short-sized; some may also have a fusion (webbed form) of their toes and fingers.

People with Pfeiffer syndrome may also experience a few other health issues. These include apnea (inability to sleep due to an improper or disturbed breathing pattern; often times, there is a stoppage of respiration and shallowness of breathing which may be experienced multiple times over a night), eyesight related problems as well as acid reflux (commonly called as heartburn characterised by a burning sensation in your chest area coupled with pain and coughs).

Types of Pfeiffer syndrome

This genetic disorder is found to occur in three distinct forms.

Type 1 form of Pfeiffer syndrome

This is a common form of this disorder. This type is also known as its mildest form. It manifests through a number of physical symptoms. In general, children with Type 1 Pfeiffer syndrome do not have problems with their mental health. Their brains are often found to function normally. Though physical problems do cause discomforts, most children may grow into adults with relatively lesser medical complications (when compared with clinical problems associated with Type 2 and Type 3 forms of Pfeiffer syndrome).

Children with Type 1 form of Pfeiffer syndrome may have a high or bulged forehead (due to an early fusion of bones in their skull), a flat rear part of the head (medically called as brachycephaly), eyes that are set widely apart (this is clinically termed as ocular hypertelorism), underdeveloped upper part of the jaw, jutting out of the lower jaw, spaced-out thumb and big toe, etc. Type 1 form of Pfeiffer syndrome may lead to a poor dental health condition (especially may result in problems related to gums) as well as hearing difficulties. The chances of accumulation of fluids inside the brain are fairly high.

Type 1 Pfeiffer syndrome is also termed as the classic version of this genetic disorder. As mentioned, children may however grow into adults with usual levels of intelligence. The major cause for this type is the changes (mutations) observed in the gene called FGFR2 (on the chromosome no. 10). The gene called FGFR1 (on chromosome no. 8) may also be a cause, but is not a very common trigger. Only a very minor share of Type 1 Pfeiffer syndrome’s incidence has been reported owing to changes in gene FGFR1.

What is the function of these two genes? These genes essentially carry the needful codes to make proteins. These proteins are needed to receive signals for bone growth. These are termed as fibroblast growth factor receiving proteins. These receptor proteins do multiple functions. One of its functions is to provide the code to develop bone cells when the fetus is well inside the mother’s womb. Without these proteins, cells may remain immature and may not eventually turn into cells of bones. Changes sensed in genes FGFR1 and / or FGFR2 can impair the codes that are essential for boosting bone formation. As a result, the infant may be born with fused bones in the skull as well as webbed feet or hands.

Advanced age of male parent is considered as a major risk that can trigger Type 1 Pfeiffer syndrome. Clinical studies reveal that changes in the sperm of older men may enhance the risk levels in children born to such males. The only comforting factor is the ability of affected individuals to live their full life (entire term of life expectancy); but this is possible only if all needful treatments are offered in a timely manner.

Type 2 form of Pfeiffer syndrome

Type 2 Pfeiffer Syndrome is often characterized by a skull shaped in the form of a cloverleaf. The symptoms are almost the same as Type 1 form of Pfeiffer syndrome, but a few of these signs may turn into acute, near-fatal risks. The child may need to be surgically operated-upon in order to survive. The signs associated with Type 2 form of this genetic disorder include premature fusion of bones of the face and skull (as mentioned, often resembling a cloverleaf), underdeveloped cognitive ability (as skull formation interrupts with the development of brain – which eventually affects functioning of the

brain), fusion of bones in joints such as knees or elbows, eyes protruding out of the child’s sockets (clinical term for this is exophthalmos), respiratory problems, etc. In some instances, the child’s nerve health may stand compromised with spinal fluids gaining entry into the brain.

Type 3 form of Pfeiffer syndrome

This type may not result in a cloverleaf shaped skull, but may cause problems to essential organs like your kidneys or lungs. The Type 3 is often characterised by severe and acute levels of several signs experienced in Type 1 and Type 2 forms of Pfeiffer syndrome. Affected children may need to be treated with multiple surgeries almost the whole of their childhood before she / he turns into an adult. Like the other types, precocious or untimely fusion of bones may deform the shape of skull. This in turn leads to lack of cognitive capabilities as well as impairing the brain function.

Diagnosis of Pfeiffer syndrome

This genetic condition is named after a geneticist based in Germany – Rudolf Arthur Pfeiffer. It was in the year 1964 that patterns of abnormal skull formation and bulging of eyes were studied in greater detail. A few individuals belonging to various generations of a single family were observed for this clinical study. This family had members with deformed hands, head and feet. Their condition spurred serious thoughts and led to a study over this pattern of genetic disorder along with the likely reasons for its incidence.

In 1993, a more definite classification of Pfeiffer syndrome was successfully documented. It facilitated the diagnosis of this genetic condition with relative ease. A proper diagnosis of the condition is needed as almost all three types are found to have a few common signs. As mentioned, the most commonly occurring symptoms are big thumbs, large sized toes and at times, webbed digits.

Type 1 Pfeiffer syndrome can be observed by an early fusion of bones that make the skull. This is often accompanied by deficiency at the middle of the face. However, the major differentiator is the presence of normal level of IQ. Individuals diagnosed with Type 1 Pfeiffer Syndrome may often live their adult life for a standard life expectancy.
Type 2 Pfeiffer Syndrome is distinctly diagnosed by the skull shaped like a cloverleaf. Apart from this, their eyes may bulge out of their sockets. Individuals with this medical condition may have acute levels of nerve health conditions. They may often meet with an untimely death.

Type 3 form of Pfeiffer syndrome can be diagnosed by the fusion of the cranial bones. Protrusion of eyes from the sockets may be more acute. This condition is considered to be not inherited (i.e., it may occur in a sporadic manner). Here again – like type 2 – health of neurological system is likely to be impaired and the odds of an untimely death are very high.

A trained and qualified physician can detect the onset of Pfeiffer syndrome through a careful examination of the child’s thumbs, toes and head. However, in order to doubly confirm it, several tests may be required. These tests are mainly performed to rule out other medical conditions, if any. The tests commonly administered onto the child are radiology and imaging based diagnostic procedures. A CT scan or an x-ray is usually taken to study your child’s head. Some physicians may also aim to confirm the genetic make-up by prescribing a few genetic tests. These are done by drawing a sample of saliva or blood to infer gene based abnormalities that may have triggered this medical condition.

Upon confirming gene level abnormalities, your physician may aim to understand your family’s medical history in greater depth. The presence of possible carriers of gene mutation – either through one parent or both – is also assessed with added focus. If genetic conditions are eliminated as possible causes, your doctor may then prescribe advanced molecular level testing of your genetic makeup.

Based on the diagnosis coupled with distinctive signs, a treatment plan is drawn out. The approach to treat is often a customized plan, specific to treat the deformities of each patient.

Treatment of Pfeiffer syndrome

There is no complete cure for this medical condition. Surgery is the most sought-after approach to treat it. The major complication to be treated is the fusion of cranial (skull) bones. This issue can be set right with multiple surgical interventions. But, these surgeries may need to be done within 3 to 4 months from the time of birth. If surgeries are not done at the earliest possible time, chances of survival of such children are fairly slim. Neonatal surgeries (especially done on skull) may be quite complicated and are considered as major procedures. Not stopping with these surgical procedures in the cranial region, more surgical interventions may be needed to set right facial defects as well as defects in the respiratory system.

It may be noted that those with Type 2 and Type 3 forms of Pfeiffer syndrome are prone to added risks of neurological problems. These factors bear huge risks that can eventually lead to an untimely and earlier death of such individuals. Children with Type 1 Pfeiffer syndrome are at relatively lesser risks of witnessing untimely deaths. However, with proper treatments – those with Type 2 and Type 3 Pfeiffer Syndrome may also reach their adulthood. In people with acute fusion of cranial bones, death often occurs due to neurological complications. Fatal outcomes may occur for people with Type 2 and Type 3 forms of Pfeiffer syndrome due to respiratory problems; mainly due to problems associated with their windpipe (trachea).

In general, the symptoms observed act as major influencers of your child’s treatment plan. A team comprising multiple medical specialists may be needed to treat the child’s condition. This team includes a child care specialist (pediatrician), neurosurgeons, plastic surgeons, dentists, psychologists, language therapists, speech coordinators and therapists amid others. The team is skewed towards surgeons because surgical procedures play an active role in most treatment plans.

Surgical approaches to treat Pfeiffer syndrome

Surgeries in the skull may invariably be needed for most children. Such procedures may need to done before the child reaches 15 to 18 months of age. These surgeries are mainly done to alter the shape of the child’s skull. Surgical procedures are also being done on very young babies – i.e., as young as 3 months or even less. Such procedures are done by making tiny apertures (openings) in the skull of the baby. However, for children who are not so young, conventional modes of skull surgeries are performed.

When deformities to be corrected are acute, the child may at times need more than three surgeries in the skull area. These surgical procedures are spaced out well so that the child can recover from the effects of each surgery with ample time in between each. Surgeries focus on unlocking the fusion of skull bones. The earlier these surgeries are done, the better it is for your child. This is because a fused skull can seriously impair the growth of the child’s brain, and thus can impair normal functioning of brain.

Surgeries to correct the accumulation of cerebrospinal fluid (CSF) deep inside the ventricles (cavities) of the child’s brain are done at the earliest possible time – i.e., soon after birth. It may be noted that higher level of pressure (termed as intracranial stress) may develop due to accumulation of extra fluids. Hydrocephalus (CSF accumulation in the brain) may be corrected by shunting excess fluids from the child’s brain to another body part. The part chosen for shunting is often tested for its absorption potential to take-in extra fluids drained from the child’s brain.

A restricted pathway of air (constricted trachea or windpipe) can lead to major side effects and respiratory problems. For instance, restricted breathing may result in very low levels of oxygen in the child’s body. If the symptoms associated with inadequate oxygen supply (discoloration, panting for breath, etc.) remain unnoticed, it can be a life-threatening situation and may at times cause fatal damages to the brain.

When Pfeiffer syndrome shows-up in an acute manner, your physician may recommend performing a surgery known as tracheostomy. This surgery is done to create an aperture (a small opening) in the child’s neck. This aperture opens into the trachea (windpipe). It is done to ease children’s breathing process. Mostly, this type of surgery is done to treat infants and toddlers who may not have multiple options to set right their breathing difficulties.

Children with Pfeiffer syndrome – though not all of them – may suffer from nasal blocks. These blocks may also pose obstacles while breathing. If left untreated, such blocks may lead to serious medical conditions such as apnea (disturbed sleep cycles due to improper breathing patterns; children may experience shallowness of breathing or a sudden inability to respire as they sleep. Children may experience such episodes of gasping for breath for multiple times during a single night). The treating physician may recommend your child to wear a specially designed face covering or mask. This mask or a face cover is used mainly when your child sleeps. In clinical terms, it is called CPAP (continuous positive airway pressure cover or mask). The facial surgery team (often, a team comprising eye surgeons, cosmetic surgeons, child care specialist amid others) may also need to set right the eye sockets to ensure eyesight of the child remains intact.

Some children may also need surgeries on their face. These are done in the middle of the face – where the nasal blockages are usually found. At times, your child’s tonsils may need to be removed to help decongest the nasal airways. Removal of adenoids (found at the rear side of nose) has also been performed to fetch desired outcomes.
Surgeries in the middle of the face are done to children who have issues in the upper jaw and nasal regions. Key objective of these surgeries is to move the child’s upper jaw bones (at times, bones near the nose) to the front. These surgeries also help in removing respiratory problems and in enhancing the facial appearances of the child.

Other elements of treatment plan for Pfeiffer syndrome

Not stopping with surgeries mentioned above, children also need a few other treatment procedures. These include surgeries to separate their webbed or fused fingers. As webbed toes are also common, surgical interventions are needed to set right their fused toes. Speech therapy may be required to help children learn how to speak. Along with speech training, the child may also require a language trainer to expedite the learning process.

As occlusion (bites) of children with Pfeiffer syndrome may not be fully developed, some dental procedures may also be required. Your child may need the care of an orthodontist (a dental specialist who sets right the misalignment of teeth) for repositioning the poor placement of teeth. Dental surgeons’ care may also be required to set right abnormal occlusion.

Rehabilitation of people with Pfeiffer syndrome

Complimentary orthopedic care as well as frequent physical therapy sessions is needed for successful rehabilitation of people after these aforesaid treatment measures and surgical interventions. All such support has been found to improve the child’s life expectancy to a greater extent. The child may need special care in the form of social support and vocational training.

Counselling is also advised to those with this medical condition. It is often not addressed to the affected individuals alone; the families of these individuals also need to be counselled in almost all instances. It is equally important for all members of the affected person’s family to get tested to detect likely genetic mutations. These tests may expose potential risks that the other members of the family may unknowingly carry in them.
It is also advised to take needful inputs from nodal support or peer groups such as children’s craniofacial association (CCA), national association for rare disorders (NORD), cleft lip and palate foundation, national craniofacial association, genetic and rare diseases information center (GARD), craniofacial support group, national hydrocephalus foundation, national institute on deafness and other communication disorders, etc.

Other disorders having similarities with Pfeiffer syndrome

Pfeiffer syndrome is also labelled as craniofacial skeletal dermatologic condition, Noack syndrome, acrocephalosyndactyly type 5 (ACSV), etc. Owing to advanced medical research, Pfeiffer syndrome is labelled under a group of genetic mutations occurring on gene called FGFR. Pfeiffer syndrome bears a few similarities with other genetic conditions such as Crouzon syndrome, Apert syndrome, Beare – Stevenson syndrome, Jackson – Weiss syndrome, FGFR2-associated coronal synostosis (isolated) syndrome, Muenke syndrome, etc.

Crouzon syndrome is a genetic disorder. Similar to Pfeiffer Syndrome, the cranial bones are fused in an improper fashion and may remain underdeveloped. As a result, people with Crouzon syndrome have deformed facial features as well as a fused skull formation. The cranial bones of affected individuals may make their skull to take the shape of a cloverleaf. The forehead of patients is round in shape as well as eyes develop into prominent features of their faces. However, the problems of webbed or fused toes and fingers are not seen among people with Crouzon syndrome. But, the most distinctive feature is the presence of cerebellar tonsils at a lower level (in comparison to the position of foramen magnum). This feature was diagnosed in as high as nearly 69% of the patients with this syndrome. Other characteristics noted among affected individuals include deformed elbows and among babies, the sutures in their cranial bones (also known as joints made of fiber) are known to close-in very early.

So, how to differentiate Crouzon syndrome from Pfeiffer syndrome? People with Crouzon syndrome are seen with almost no deformities on their feet and hands. They might appear to be as normal as individuals who do not have any such genetic disorders.
Consumption of alcohol during maternity period is widely believed as one strong reason for this condition to show up among new born babies. It is known known to occur due to autosomal dominance triggered by a gene called fibroblast growth factor receptor 2 (FGFR2) located in chromosome labelled as 10q25 / 10q26. This condition is called thus after L. E. Octave Crouzon, a physician who worked in France in 1912.

Crouzon syndrome showing up with skin disorders: This is clinically labelled as Crouzon syndrome with acanthosis nigricans. This condition shows up with all the signs linked to Crouzon syndrome (listed above); in addition, dark and thick folds of skin are seen. This condition is usually associated with changes or mutations in the gene labelled as FGFR3.

People with Apert syndrome possess a stretched forehead (also, flat at times). This condition also leads to abnormal formation of sockets (set apart with a wide distance between them) as well as a delayed development of organs in the middle of your facial area. Owing to shallowness of their sockets, eyes become even more protruded. This genetic disorder is observed rarely i.e., 1 in 75,000 deliveries. Advanced age of parents (especially the male parent) is believed as a major cause for this condition to occur. This is also characterised by cardiac disorders (as a congenital anomaly) as well as disorders associated with the central nervous system (CNS) of the newly born infant. Other characteristics of this syndrome are poorly developed cognitive capabilities, eye sockets that are set apart, a raised forehead, shape of the head resembles a tower, protrusion of facial organs, etc.

Beare – Stevenson syndrome shows up as an early (i.e., untimely) fusion of the skull bones. It also shows up as disorders related to the skin. This untimely fusion of cranial bones deters the full development of your face and head. Several other signs that are associated with this syndrome include sockets that are widely set apart, eyes that bulge out, cloverleaf-like head as well as hearing impairment. The disorders linked to skin are clinically referred to as gyrata cutis. Beare – Stevenson syndrome affects your skin by making it wrinkled. A furrowed skin formation is often noticed on the soles of your feet, palms as well as on your face. Moreover, a velvet textured skin can take shape near your genital areas and limbs. This velvety skin condition is clinically termed as acanthosis nigricans. Other salient characteristics of the Beare – Stevenson syndrome are constricted airways, blocks in nasal cavities and disorders associated with anus or genitals.

Jackson – Weiss syndrome is also characterized by fusion of skull bones, bulged forehead and spaced out eyes. One key differentiator of this syndrome is the presence of a flat mid segment of the child’s face. The big toe (usually shows up in bigger than normal size) may be seen distanced off from the other digits. Though your hands and fingers may not show deformities, toes may often take a webbed (fused) form. In case of webbing, the big toe may be seen webbed with the second toe; however, at times the big toe is also seen webbed with 2nd as well as 3rd toes.

IQ levels are found to be at standard levels and the life expectancy is also normal. However, loss of hearing may be a common sign of this disorder. The condition may either show up as moderate or acute, depending on your family history – especially clinical history of very close relatives. This condition is linked to the mutations seen in gene FGFR2.

Muenke syndrome is another genetic condition that resembles to a greater extent with Pfeiffer syndrome. This is also signified by poor development of cranial bones. A small percentage of people with Muenke syndrome may have a bloated head (enlarged in size). Though IQ levels are often seen at a normal level, children may show problems in cognition as well as hearing difficulties. It may also be helpful to note that a minor proportion of people may carry this mutated gene without exhibiting any of the common signs associated with this genetic disorder. This syndrome has been observed in nearly 1 among 32,000 babies. In terms of incidence, this syndrome accounts for less than 5% of all cases of fusion of cranial bones (clinically referred as craniosynostosis). This condition is linked to the mutation of a gene labelled as FGFR3.

A condition called FGFR2-associated coronal synostosis (isolated form) is also an autosomal genetic ailment. This condition also leads to an earlier fusion of cranial bones. This untimely fusion is observed between both the ears – running across top of the head. This specific mode of fusion is termed as coronal craniosynostosis. Apart from this symptom, the child may have eyes that are set widely apart. Otherwise, no other disabilities or abnormal growth are noticed among children with this condition. It is linked to the mutations observed in FGFR2 gene.

Though not linked to the FGFR gene, Saethre – Chotzen syndrome (also called as type III acrocephalosyndactyly); this condition shows up as deformities of skull and digits. This is a more common form of disorder that affects the skull bones. This can affect females and males alike. This is believed to occur due to gene level changes or mutations in the chromosome labelled 7p21. It is often passed on by a parent as an autosomal pattern.

In essence, genetic ailments are caused due to mutation of genes. Gene mutation may be passed on from one of your parents (who may have a disorder) or from both parents who may be carriers of such genes. Pfeiffer syndrome is a rare kind of genetic condition, seen in 1 among 100,000 children. The common cause is the mutation of a gene called FGFR2; this apart, mutations in a gene called FGFR1 may also be a reason. Pfeiffer syndrome is a medical condition that interferes in skull development. Face and head of the affected individual may not take a normal shape. As a result, people with Pfeiffer Syndrome may have wide-set, bulged eyes and a high forehead. Their thumb and big toe may be spaced away from other digits. People with this syndrome may experience a few other issues like sleep apnea, acid reflux and vision related problems.

This condition can show up in three distinct forms. Type 1 form of Pfeiffer syndrome: the most common form of this disorder is also the mildest. It shows up as physical symptoms such as bulged forehead, a flat head (on the rear side), eyes that are set apart, deformed upper jaw, jutting lower jaw, spaced-out toes and fingers. This form of Pfeiffer syndrome may also cause bad dental health condition as well as hearing issues. Type 2 form of Pfeiffer syndrome: This type is characterized by premature fusion of bones of the face and skull (shaped like a cloverleaf), underdeveloped cognitive capability, fusion of bones in knees or elbows, eyes protruding out of sockets, respiratory issues, etc.
Type 3 form of Pfeiffer syndrome: This condition is characterised by deformed skull, lack of cognitive capabilities as well as impaired brain function.

Almost all instances of Type 2 and Type 3 of Pfeiffer syndrome are due to newly mutated genes i.e., without either or both of the parents acting as carriers. Parenting at a fairly advanced age is believed to be a reason for the incidence of Pfeiffer syndrome. If one of the parents is a carrier, the risk factors associated with the new born being affected is 50%. This risk looms at large during each pregnancy. The risk for a new born does not get altered based on the gender i.e., regardless of the new-born baby is a girl or boy, risk levels are just about the same. Pfeiffer syndrome Type 1 is linked to mutations observed in genes FGFR1 and FGFR2. However, likelihood of incidence of Type 2 and Type 3 of Pfeiffer syndrome is associated with mutated FGFR2 gene.

A CT scan or an x-ray can help in assessing your child’s skull. Doctors also aim to confirm the genetic condition by administering gene tests, by drawing a sample of saliva or blood. The presence of carriers of a gene mutation is assessed in detail. Based on complications diagnosed, a customized plan is drawn out, specific to treat the deformities of each patient.

There is no complete cure for this genetic condition. More often, surgery is a sought-after approach. The fused cranial (skull) bones are set right with multiple surgical interventions. However, surgeries may need to be performed in 3 to 4 months from the time of the infant’s birth. If delayed, chances of baby’s survival become slim. Surgeries done on new born babies (especially on the skull) can get complicated. Not stopping with these surgical procedures in the cranial region, more procedures may need to be done to set right facial defects as well as defects in the respiratory system.

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